Variant classification summary

NM_001354609.1:c.1024A>G

BRAF · NP_001341538.1:p.(Ile342Val) · NM_001354609.1

GRCh37: chr7:140494224 T>C · GRCh38: chr7:140794424 T>C

Gene: BRAF Transcript: NM_001354609.1

Final call

VUS

Variant details

Gene

BRAF

Transcript

NM_001354609.1

Protein

NP_001341538.1:p.(Ile342Val)

gnomAD AF

5.700272249959416e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRAF c.1024A>G (p.Ile342Val) variant has been reported in ClinVar, where it is classified overall as a variant of uncertain significance, including by the ClinGen RASopathy Variant Curation Expert Panel, with one additional likely benign clinical laboratory submission.

2

This variant is present in gnomAD at low frequency, with an allele frequency of 0.00389% in v2.1 and 0.00570% in v4.1; these values are below the BRAF RASopathy BS1 threshold of 0.025% and BA1 threshold of 0.05%, but the variant is not absent from controls, so PM2 is not met.

3

No variant-specific result from an approved RASopathy VCEP functional assay was identified for p.Ile342Val, so functional evidence was insufficient to apply PS3.

4

Computational evidence is mixed: REVEL is 0.269 and BayesDel is -0.184306, which do not support a damaging missense effect, but SpliceAI predicts possible splice impact with a max delta score of 0.58; therefore, neither PP3 nor BP4 was applied.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This variant is a missense substitution, and the BRAF RASopathy framework marks PVS1 as not applicable. The generic PVS1 scaffold also indicates that c.1024A>G does not fall into a null-variant category such as nonsense, frameshift, or canonical splice-site loss.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 is not met.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with sufficient parental testing and phenotype detail was identified for this variant, so PS2 was not assessed.	clinvar cspec
PS3	Not assessed	No variant-specific result from an approved functional assay was identified for p.(Ile342Val), so PS3 was not assessed.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	No exact-variant case series or case-count evidence showing enrichment in affected individuals was identified, so PS4 was not assessed.	clinvar cspec
PM1	Not met	The variant affects codon 342, which is outside the BRAF PM1-eligible regions listed in the RASopathy framework, including exon 6, exon 11, the P-loop (amino acids 459-474), and the CR3 activation segment (amino acids 594-627). Cancer Hotspots also did not identify this residue as a significant hotspot.	cspec hotspots
PM2	Not met	This variant is present in population databases and therefore is not absent from controls. In gnomAD, the allele frequency is 0.00389% in v2.1 and 0.00570% in v4.1, so the RASopathy PM2 rule is not met.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in this BRAF RASopathy framework.	cspec
PM4	N/A	This is a single amino acid substitution and does not change protein length, so PM4 is not applicable.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at the same residue was identified in the available evidence, so PM5 is not met.	cspec clinvar pm5_candidates
PM6	Not assessed	No apparently de novo occurrence without confirmed parentage was identified for this variant, so PM6 was not assessed.	clinvar cspec
PP1	Not assessed	No segregation data or informative meioses were identified for this variant, so PP1 was not assessed.	clinvar cspec
PP2	Not assessed	PP2 was not assessed because a BRAF missense constraint value meeting the framework threshold was not identified in the reviewed evidence.	cspec
PP3	Not met	Available computational evidence does not meet the BRAF RASopathy PP3 rule. REVEL is 0.269, which is below the PP3 threshold of 0.7, and BayesDel is -0.184306, which does not support a damaging missense effect. Although SpliceAI predicts possible splice impact with a max delta score of 0.58, this alone does not satisfy the governing PP3 rule for this missense variant.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in this BRAF RASopathy framework.	cspec
PP5	N/A	PP5 is not applicable in this BRAF RASopathy framework.	cspec
BA1	Not met	The population frequency is below the BRAF RASopathy BA1 threshold. In gnomAD v4.1, the allele frequency is 0.00570%, which is below the 0.05% BA1 threshold.	gnomad_v4 cspec
BS1	Not met	The population frequency is below the BRAF RASopathy BS1 threshold. In gnomAD v4.1, the allele frequency is 0.00570%, which is below the 0.025% BS1 threshold.	gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in a sufficient number of unaffected individuals to meet the points-based BS2 rule, so BS2 was not assessed.	cspec gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applicable in this BRAF RASopathy framework.	cspec
BS4	Not assessed	No family data showing lack of segregation were identified for this variant, so BS4 was not assessed.	clinvar cspec
BP1	N/A	This is a missense variant, whereas BP1 in the RASopathy framework is reserved for truncating variants in genes where gain-of-function missense variants are the established mechanism.	cspec
BP2	Not assessed	No phase data or observation with another pathogenic variant were identified, so BP2 was not assessed.	cspec
BP3	N/A	BP3 is not applicable in this BRAF RASopathy framework.	cspec
BP4	Not met	Computational evidence is mixed and does not support applying BP4. REVEL is 0.269, which is within the BP4 threshold of 0.3 or lower, and BayesDel is -0.184306, which does not support a damaging missense effect; however, SpliceAI predicts possible splice impact with a max delta score of 0.58. Because the computational results are not uniformly benign, BP4 is not applied.	cspec revel bayesdel spliceai
BP5	Not assessed	No alternate molecular explanation or points-based BP5 evidence was identified for this variant, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not applicable in this BRAF RASopathy framework.	cspec
BP7	N/A	This is a missense variant, not a synonymous or intronic change, so BP7 is not applicable.	cspec spliceai

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